Antiplatelet Agents & Thrombolytics

Platelet activation and drug targets

The platelet plug. Endothelial injury exposes collagen and von Willebrand factor (vWF), which platelets capture through glycoprotein Ib. Adherent platelets release thromboxane A2 (TXA2, made via COX-1) and ADP (acting on P2Y12 receptors) and respond to thrombin through protease-activated receptor-1 (PAR-1). These signals converge on GPIIb/IIIa, which changes shape and binds fibrinogen, bridging neighboring platelets. Intracellular cAMP is a brake, so drugs that raise it (phosphodiesterase inhibitors) also blunt activation. Antiplatelet drugs mainly prevent platelet-rich arterial thrombi in coronary, cerebral, and peripheral arteries.

Aspirin: mechanism, toxicity, and overdose

Mechanism. Aspirin irreversibly acetylates a serine residue in COX-1 (and COX-2), blocking TXA2 synthesis. Anucleate platelets cannot make new COX, so one dose disables them for their 7–10-day lifespan, and function returns only as new platelets appear. Nucleated endothelial cells resynthesize COX, so low doses spare vascular prostacyclin. Aspirin prolongs the bleeding time but leaves PT and aPTT normal. Other NSAIDs inhibit COX reversibly, and ibuprofen taken before aspirin can occupy the COX-1 channel and blunt its effect. Uses include ACS, secondary prevention of MI and ischemic stroke, peripheral artery disease, and Kawasaki disease.

GI injury. Loss of gastroprotective prostaglandins reduces mucus, bicarbonate, and mucosal blood flow; with platelet inhibition, this produces erosive gastritis, peptic ulcers, and GI hemorrhage even at low doses. Risk rises with age, prior ulcer, corticosteroids, and anticoagulants; a proton pump inhibitor lowers it.

Reye syndrome. In children and teenagers with influenza or varicella, aspirin can trigger mitochondrial injury with microvesicular hepatic steatosis, hyperammonemia, hypoglycemia, and encephalopathy with cerebral edema. Aspirin is avoided under age 18 except in Kawasaki disease.

Aspirin-exacerbated respiratory disease (AERD). Asthma, chronic rhinosinusitis with nasal polyps, and respiratory reactions to aspirin or other COX-1 inhibitors form Samter triad. Blocking COX diverts arachidonic acid to 5-lipoxygenase and cysteinyl leukotrienes; the reaction is pseudoallergic, not IgE-mediated. Leukotriene modifiers (montelukast, zileuton) help, and aspirin desensitization is an option.

Salicylate poisoning. Tinnitus is an early sign. Salicylates stimulate the medullary respiratory center (respiratory alkalosis first), then uncouple oxidative phosphorylation, generating lactic acid, ketoacids, and heat: an anion-gap metabolic acidosis with hyperthermia. Severe poisoning adds altered mental status, cerebral edema, and noncardiogenic pulmonary edema.

P2Y12, GPIIb/IIIa, PDE, and PAR-1 inhibitors

P2Y12 blockers. ADP acting on P2Y12 activates GPIIb/IIIa; blocking the receptor prevents ADP-driven aggregation. With aspirin, these drugs form dual antiplatelet therapy after ACS and coronary stenting.

Details. Loss-of-function CYP2C19 alleles leave poor metabolizers with little active clopidogrel and more stent thrombosis. Prasugrel is more potent but raised intracranial hemorrhage in patients with prior stroke or TIA. Ticagrelor's dyspnea is attributed to adenosine accumulation. Cangrelor is an IV, reversible P2Y12 blocker used during PCI. Ticlopidine, the first thienopyridine, required CBC monitoring and was replaced by the safer clopidogrel.

GPIIb/IIIa inhibitors. Abciximab (a chimeric antibody Fab), eptifibatide (a cyclic peptide), and tirofiban (a nonpeptide) block fibrinogen binding to GPIIb/IIIa, preventing aggregation whatever the stimulus. They are given IV during PCI or high-risk ACS; bleeding and acute, sometimes profound thrombocytopenia are the main toxicities.

Glanzmann thrombasthenia (congenital GPIIb/IIIa deficiency) mimics these drugs: normal platelet count, no aggregation to any agonist, but normal ristocetin agglutination.

PDE inhibitors. Cilostazol inhibits PDE3, raising cAMP in platelets and arterial smooth muscle; the antiplatelet and vasodilator effects lengthen walking distance in intermittent claudication. Oral PDE3 inhibitors increased mortality in heart failure, so cilostazol is contraindicated in heart failure of any severity; headache, palpitations, and diarrhea are common. Dipyridamole blocks adenosine reuptake and inhibits PDE; extended-release dipyridamole with aspirin is used for secondary stroke prevention, and IV dipyridamole is a pharmacologic stress agent (coronary steal). Headache and flushing are typical.

Vorapaxar. This PAR-1 antagonist blocks the platelet thrombin receptor and is added to aspirin or clopidogrel for secondary prevention after MI or in peripheral artery disease. Prior stroke, TIA, or intracranial hemorrhage contraindicates it.

Thrombolytics

Mechanism. Alteplase (recombinant tissue plasminogen activator), reteplase, and tenecteplase (single bolus, more fibrin-specific, longer half-life) convert fibrin-bound plasminogen to plasmin, a serine protease that lyses fibrin and releases D-dimer and other fibrin degradation products (FDPs). The older streptokinase is bacterial, antigenic, and not fibrin-specific. Circulating plasmin also degrades fibrinogen, so PT and aPTT rise and fibrinogen falls, while the platelet count is unchanged.

Indications. Acute ischemic stroke within 4.5 hours of last known well (blood pressure must be below 185/110 mm Hg), STEMI when timely primary PCI is unavailable, and massive pulmonary embolism with shock.

Contraindications. Because bleeding is the central risk, thrombolysis is withheld with:

• Any prior intracranial hemorrhage, or ischemic stroke within 3 months
• Intracranial neoplasm or vascular malformation
• Active internal bleeding (menstruation excepted) or suspected aortic dissection
• Recent intracranial or spinal surgery, major surgery, or significant head trauma
• Severe uncontrolled hypertension

Menstruation, older age, and diabetic retinopathy are not absolute contraindications; a remote hemorrhagic stroke is.

Reversal. For thrombolytic-associated bleeding, stop the infusion, give cryoprecipitate (fibrinogen, factor VIII, von Willebrand factor, factor XIII), and add an antifibrinolytic: aminocaproic acid or tranexamic acid, lysine analogs that occupy plasminogen's lysine-binding sites so it cannot attach to fibrin. Protamine, vitamin K, and idarucizumab reverse heparin, warfarin, and dabigatran, not fibrinolysis. Tranexamic acid is also used in trauma, postpartum hemorrhage, and dental procedures in hemophilia.